Complications Of Vascular Disease Research Articles

Rehabilitation experiences following major lower limb amputation due to complications of vascular disease: a UK qualitative study

Purpose Rehabilitation experiences of lower limb amputees with poorer physical health have not been fully explored. This study aimed to qualitatively explore experiences of rehabilitation amongst patients who had recently undergone amputation due to complications of vascular disease. Methods Semi-structured, face-to-face interviews were conducted with 14 patients participating in the PLACEMENT randomised controlled feasibility trial (ISRCTN: 85710690; EudraCT: 2016-003544-37), which investigated the effectiveness of using a perineural catheter for postoperative pain relief following major lower limb amputation. Framework analysis was used to identify key themes and compare participant data. Findings Three main themes and corresponding sub-themes were identified: (i) other patients as inspiration; (ii) other patients as competition; and (iii) imagined futures. Perceptions relating to other patients played a key role in rehabilitation, providing a source of motivation, support, and competition. Participants’ imagined futures were uncertain, and this was compounded by a lack of information and delays in equipment and/or adaptations. Conclusions Findings highlight the importance of fellow patients in supporting rehabilitation following lower limb amputation. Enabling contact with other patients should thus be a key consideration when planning rehabilitation. There is a clear unmet need for realistic information relating to post-amputation recovery, tailored to the needs of individual patients.

Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study.

COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19. As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2-3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics-cfPWV, AIx@HR75, and cDBP as well as DBP and MAP-responded to a mild COVID-19 disease. The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (pregression_models ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2-3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP). The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.

A fluorescent nano vector for early diagnosis and enhanced Interleukin-33 therapy of thoracic aortic dissection

Thoracic aortic dissection (TAD) is the most devastating complication of vascular disease. The accuracy of the clinical diagnosis and treatment of TAD at the early stage is still limited. Herein, we report a nano-delivery strategy for early diagnosis and the first case of interleukin-33 (IL-33) based therapy for the effective intervention of TAD. A targeted fluorescent nano vector (FNV) is designed to co-assemble with IL-33, which protects IL-33 and prolongs its half-life. With specific targeting ability to the thoracic aorta, FNV can diagnose TAD at its early stage through fluorescent imaging. FNV@IL-33 nanocomplex presents better therapeutic effects on mice TAD progression compared with that of IL-33 alone by reducing smooth muscle apoptosis. Administration of FNV@IL-33 two weeks before onset, the development of TAD is greatly intervened. Our study provides a novel approach for early diagnosis and effective IL-33 therapy of TAD, which opens attractive opportunities for clinical prevention of cardiovascular diseases.

Complications of Vascular Disease.

Vascular diseases and their sequelae increase perioperative risk for noncardiac surgical patients. In this review, the authors discuss vascular diseases, their epidemiology and pathophysiology, risk stratification, and management strategies to reduce adverse perioperative outcomes.

Saving limbs and lives: Building out an Ontario lower limb preservation strategy

There are over 1,200 non-traumatic major lower-limb amputations every year in Ontario, the majority resulting from complications of vascular disease, diabetes or both. This equates to one lower-limb amputation every seven hours, and results in approximately $140 million in direct amputation health-care costs annually. CorHealth Ontario is collaborating with a provincial Advisory Committee to develop a multi-year provincial Lower-Limb Preservation Strategy. The strategy aims to facilitate a coordinated, integrated and patient-centred approach to lower-limb preservation care in Ontario.

Analgesic activity and anti-inflammatory activity of methanolic extract of plant Sida cordata in carrageenan-induced paw edema in rats

India has rich heritage of use of medicinal plants in clinical practices since ancient times. Diabetes mellitus is a group of syndromes characterized by hyperglycemia, altered lipid, carbohydrate and protein metabolism, and an increased risk of vascular disease complications. More than 400 plant species have been recorded to display hypoglycemic effects, but only a few of them have been investigated. Although many drugs are available to control the diabetes but has several adverse effects. The plant Sida cordata activities have been reported such as Antibacterial, Antitumor, Antifungal, Antiulcer, Antitussive, Anti-inflammatory, Anti-malarial, Anti-oxidant, Analgesic, Antidepressant, Antihyperglycemic, Hepatoprotective in ayurvedic system of medicine. This research was conducted undertaken In order to investigate the anti-diabetic activity of methnolic extract of Sida cordata. The two dose (100 and 200 mg/kg) methnolic extract of Sida cordata used for treatment of Alloxan induced diabetic rats. The glucose level was significantly (p<0.01) high in Alloxan control rats when opposed to normal control. But the level of glucose was significantly (p<0.01) decreased after 7th day in diabetic rats treated with methanol extract (200 mg/kg) as compared with diabetic control rats.

Antiplatelet Therapy for Secondary Prevention of Vascular Disease Complications.

Platelets are activated upon interaction with injured vascular endothelium to form a primary hemostatic plug. Pathogenic thrombosis driven by platelet aggregation can occur in the setting of vascular disease leading to ischemic events. The use of antiplatelet agents has become a mainstay for prevention of the secondary complications of vascular disease. This review summarizes seminal and recent literature related to this area. Aspirin is a cornerstone of antiplatelet therapy for coronary artery disease and cerebrovascular disease for prevention of myocardial infarction, stroke, and vascular death. Alternative antiplatelet agents have shown promise for use in patients with peripheral artery disease though further validation is necessary. Dual antiplatelet therapy (DAPT) with clopidogrel, prasugrel, or ticagrelor, and aspirin demonstrates benefit in patients with higher thrombotic risk. However, use of DAPT predictably increases bleeding risk, thus limiting mortality benefit. Individualization of DAPT to patient-specific features is an area of active research with the development the DAPT score and pharmacogenomic approaches. Application of pharmacogenetic data could allow for a precision medicine approach to tailoring antiplatelet therapy. Recommendations for management of cardiovascular, cerebrovascular, and peripheral artery disease are largely based on large-scale randomized control trials and meta-analyses. Seminal trials have largely focused on prevention of vascular events including non-fatal MI, stroke, and vascular death in subsets of patients with cardiovascular disease. Data from these trials along with smaller studies have driven recommendations for secondary prevention management in patients with cerebrovascular and peripheral artery disease.

Invited commentary

This carefully performed analysis of the National Inpatient Sample database highlights both the strengths and weaknesses of “big data” in our quest for improving patient outcomes from the complications of vascular disease. Despite significantly greater comorbidities, the thoracic endovascular aortic repair (TEVAR) group had better hospital outcomes than the group undergoing open repair, in all venues. The substantial increase in TEVAR over nonoperative management reflects the physician's and patient's perception that “minimally invasive” techniques deserve application in populations that were previously believed unfit for open repair, and the decreased in-hospital mortality would appear to support this position. What is reassuring is that improved early outcomes support that TEVAR is a welcome addition to the management of a complex and often fatal problem. What the study does not address—and by the nature of the database is incapable of doing—is the long-term outcome for the patients offered treatment, particularly for the very elderly, who have experienced the greatest increase in intervention. With acute renal failure and respiratory failure occurring in 22% and 33%, respectively, and discharge to home of only 27%, the long-term impact on quality of life may not reflect the same optimism associated with a decreasing hospital mortality. Whereas the introduction of less invasive therapies has clearly broadened the eligibility for patients at high risk or unfit for traditional open repair, we must be cautious to ensure that short-term markers of success, particularly in-hospital mortality, are balanced against patient-centered expectations. Hospital readmissions, a useful surrogate for a successful result, cannot be linked with the National Inpatient Sample database. It is possible that using linked hospital data will improve our understanding of the long-term outcomes of our interventions. Using the Medicare/Centers for Medicare and Medicaid Services database, Schaffer et al1Schaffer J.M. Lingala B. Miller D.C. Woo Y.J. Mitchell R.S. Dake M.D. Midterm survival after thoracic endovascular aortic repair in more than 10,000 Medicare patients.J Thorac Cardiovasc Surg. 2015; 149: 808-820Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar demonstrated substantially worse early and midterm (5-year) mortality for TEVAR patients presenting with rupture. Crude measures of late mortality, however, do little to help us understand which patients recover to independence and which have a significant reduction in the quality of their lives. Predictors of outcome with elective abdominal aneurysm repair have begun to explore functional status2Endicott K.M. Emerson D. Amdur R. Macsata R. Functional status as a predictor of outcomes in open and endovascular abdominal aortic aneurysm repair.J Vasc Surg. 2017; 65: 40-45Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar and frailty3Arya S. Kim S.I. Duwayri Y. Brewster L.P. Veeraswamy R. Salam A. et al.Frailty increases the risk of 30-day mortality, morbidity, and failure to rescue after elective abdominal aortic aneurysm repair independent of age and comorbidities.J Vasc Surg. 2015; 61: 324-331Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar as independent predictors of poor outcomes, with impact beyond the traditional risks of heart failure, cerebrovascular diseases, and renal failure. The accuracy of several ruptured aneurysm scoring systems to predict futility has been challenged,4Thompson P.C. Dalman R.L. Harris E.J. Chandra V. Lee J.T. Mell M.W. Predictive models for mortality after ruptured aortic aneurysm repair do not predict futility and are not useful for clinical decision making.J Vasc Surg. 2016; 64: 1617-1622Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar and this relates only to mortality. It remains the responsibility of the surgeon to help patients understand how their individual situation relates to predictive algorithms.5Sniderman A.D. D'Agostino Sr., R.B. Pencina M.J. The role of physicians in the era of predictive analytics.JAMA. 2015; 314: 25-26Crossref PubMed Scopus (50) Google Scholar We owe it to our patients to place our ability to perform a procedure in the context of our patient's goals, it is to be hoped with sound predictive data to support these decisions. The impact of endovascular repair on management and outcome of ruptured thoracic aortic aneurysmsJournal of Vascular SurgeryVol. 66Issue 2PreviewThoracic endovascular aortic repair (TEVAR) has become an alternative to open repair for the treatment of ruptured thoracic aortic aneurysms (rTAAs). The aim of this study was to assess national trends in the use of TEVAR for the treatment of rTAA and to determine its impact on perioperative outcomes. Full-Text PDF Open Archive

Intravital Microscopy and Thrombus Induction in the Earlobe of a Hairless Mouse

Thrombotic complications of vascular diseases are one leading cause of morbidity and mortality in industrial nations. Due to the complex interactions between cellular and non-cellular blood components during thrombus formation, reliable studies of the physiology and pathophysiology of thrombosis can only be performed in vivo. Therefore, this article presents an ear model in hairless mice and focuses on the in vivo analysis of microcirculation, thrombus formation, and thrombus evolution. By using intravital fluorescence microscopy and the intravenous (iv) application of the respective fluorescent dyes, a repetitive analysis of microcirculation in the auricle can easily be performed, without the need for surgical preparation. Furthermore, this model can be adapted for in vivo studies of different issues, including wound healing, reperfusion injury, or angiogenesis. In summary, the ear of hairless mice is an ideal model for the in vivo study of skin microcirculation in physiological or pathophysiological conditions and for the evaluation of its reaction to different systemic or topical treatments.

Intravital Microscopy and Thrombus Induction in the Earlobe of a Hairless Mouse.

Thrombotic complications of vascular diseases are one leading cause of morbidity and mortality in industrial nations. Due to the complex interactions between cellular and non-cellular blood components during thrombus formation, reliable studies of the physiology and pathophysiology of thrombosis can only be performed in vivo. Therefore, this article presents an ear model in hairless mice and focuses on the in vivo analysis of microcirculation, thrombus formation, and thrombus evolution. By using intravital fluorescence microscopy and the intravenous (iv) application of the respective fluorescent dyes, a repetitive analysis of microcirculation in the auricle can easily be performed, without the need for surgical preparation. Furthermore, this model can be adapted for in vivo studies of different issues, including wound healing, reperfusion injury, or angiogenesis. In summary, the ear of hairless mice is an ideal model for the in vivo study of skin microcirculation in physiological or pathophysiological conditions and for the evaluation of its reaction to different systemic or topical treatments.

Bias in the use of randomized trials for carotid stenosis management.

BackgroundCarotid artery procedures, such as surgery and stenting, although associated with significant risks and costs, are often recommended in guidelines which cite12- to 34-year-old randomized trial evidence of benefit; however, these recommendations exist although there is no evidence these procedures benefit patients who receive only current optimal medical treatment (encouragement of a healthy lifestyle and appropriate use of medication).ObjectiveTo examine whether bias exists in the use of randomized trial evidence and its impact on guideline recommendations.Material and methodsExamples of how bias underpins endorsement of carotid procedures for patients with asymptomatic or symptomatic carotid stenosis were sought from available literature. .ResultsMany forms of procedural bias were identified involving the need for randomized trials, and their design and interpretation. Fundamental problems included failure to first adequately measure outcomes with non-invasive treatment alone, lack of appreciation of quality non-randomized trial measurements of risk in determining need for randomized trials and their applicability in routine practice, poor randomized trial methods with biased comparisons, inaccurate definitions of target populations, confusion of efficacy and safety outcomes, too much reliance on statistical rather than clinical significance and biased use of terminology to make procedures sound more effective.ConclusionProcedural bias in design and interpretation of randomized trials has resulted in widespread loss of understanding of how to optimize outcomes in patients with carotid artery stenosis. Current guidelines reflect the cumulative impact of this bias and are an excellent starting point for efforts to improve prevention of stroke and other vascular disease complications; however, there is also need for clinicians, policy makers, health service funding bodies, educators and the general public to assist.

The Heart in Inflammatory Myopathies

Systemic autoimmune diseases are becoming increasingly linked to accelerated risks of cardiovascular disease and events. What is apparent from the above review is that the IIM are not an exception to this growing pattern. Although not always clinically apparent, there seems to be a large percentage of patients who have subclinical CV involvement. Many of the traditional risk factors for CAD, such as hypertension and hyperlipidemia, are associated with developing cardiac involvement in patients with IIM. At this time, it is unclear how much of the atherosclerotic CV morbidity and mortality in IIM patients is driven by traditional CV risk factors versus the effects of chronic systemic inflammation from the underlying IIM. The effects of immunosuppression on cardiac disease and events in IIM patients requires further investigation in carefully controlled studies. IIM patients with cardiac involvement are at increased risk for overall mortality when compared with IIM patients without CV disease. The risk of severe cardiac and vascular disease complications seems to be higher than that of the general population. Treatments can be focused on preventing traditional cardiovascular risk factors including avoidance of corticosteroids when possible, although this task remains challenging in IIM as is true of other rheumatic diseases. Once complications do develop, they should be managed similarly to patients without IIM. The use of statins for hyperlipidemia and atherosclerosis in IIM is an area that is in need of further investigation, although initial work suggests that their use is not uncommon by IIM specialists. Further work is needed to determine whether aggressive immunosuppressive treatment of patients with subclinical cardiac disease will lead to better outcomes. Work is also needed in the area of better laboratory, imaging, and serologic testing to identify patients at risk for the worst cardiovascular complications. At this point, based on the body of evidence reviewed here and elsewhere, it is imperative that physicians treating IIM patients performa routine cardiovascular risk assessment at the onset of diagnosis. Appropriate diagnostic and monitoring studies should be performed on those patients who screening history or examination is suggestive of cardiac involvement.

ANTIDIABETIC EFFECT OF Ubidecarenone IN RATS

s. PHYTOPHARM 2012 M 70 Obzory po kliniceskoj farmacologii i lekarstvennoj terapii [Reviews of clinical pharmacology and drug therapy] ТОМ 10/2012/2 zantherin А 0,021–0,024, shizandrin А 0,017–0,019, shizandrin b 0,074–0,095. Total content of shizandrins calculated in shizandrol A equivalents was about 0.3 %. Relations between individual lignans were about 1:1:0,2:0,2:1. This is optimal for adaptogenic properties of Shizandra drugs (2). Thus, fatty oils are effective for shizandra lignans extraction. The method was proposed for extract standardization and validated according to the iCh guidelines on the validation of analytical methods and (3).

Neurovascular Coupling in Cognitive Impairment Associated With Diabetes Mellitus

Although it is feared that diabetes-induced cognitive decline will become a major clinical problem worldwide in the future, the detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, with not only macrovascular but also microvascular disorders, vascular disorders in the brain are considered to be one of the mechanisms in diabetes-induced cognitive impairment. Indeed, disruption of the blood-brain barrier (BBB) has been observed in some diabetic patients and experimental diabetes models. Moreover, white matter lesions, part of the evidence of BBB dysfunction, are reported to be observed more frequently in patients with diabetes. Animal studies demonstrate that diabetes enhances BBB permeability through a decrease in the level of tight junction proteins and an increase in matrix metalloproteinase activity. However, there are several reports indicating that BBB disruption does not occur with diabetes. Therefore, the association of BBB breakdown with diabetes-induced cognitive impairment is not conclusive. Recently, neuronal diseases involving dementia have been induced experimentally through dysfunction of neurovascular coupling, which involves blood vessels, astrocytes and neutrons. Diabetes-induced cognitive decline may be induced via disruption of neurovascular coupling, with not only vascular disorder but also impairment of astrocytic trafficking. Here, the relation between vascular disorder and cognitive impairment in diabetes is discussed.

Novel astaxanthin prodrug (CDX-085) attenuates thrombosis in a mouse model

Background Cardiovascular disease remains the leading cause of morbidity and premature mortality in most industrialized countries as well as in developing nations. A pro-oxidative state appears to promote and/or exacerbate vascular disease complications. Furthermore, a state of low-grade chronic inflammation can promote increased oxidative stress and lead to endothelial cell and platelet dysfunction ultimately contributing to thrombogenesis. Objectives In this study, the effect of a proprietary astaxanthin prodrug (CDX-085) on thrombus formation was investigated using a mouse model of arterial thrombosis. The influence of free astaxanthin, the active drug of CDX-085, on human endothelial cells and rat platelets was evaluated to investigate potential mechanisms of action. Methods and results Oral administration of CDX-085 (0.4% in chow, approximately 500 mg/kg/day) to 6-8 week old C57BL/6 male mice for 14 days resulted in significant levels of free astaxanthin in the plasma, liver, heart and platelets. When compared to control mice, the CDX-085 fed group exhibited significant increases in basal arterial blood flow and significant delays in occlusive thrombus formation following the onset of vascular endothelial injury. Primary human umbilical vein endothelial cells (HUVECs) and platelets isolated from Wistar-Kyoto rats treated with free astaxanthin demonstrated significantly increased levels of released nitric oxide (NO) and significantly decreased peroxynitrite (ONOO-) levels. Conclusion Observations of increased NO and decreased ONOO- levels in endothelial cells and platelets support a potential mechanism of action for astaxanthin (CDX-085 active drug). These studies support the potential of CDX-085 and its metabolite astaxanthin in the treatment or prevention of thrombotic cardiovascular complications.

The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants

Complications of vascular diseases, including atherosclerosis, are the number one cause of death in Western societies. Dysfunction of endothelial cells is a critical underlying cause of the pathology of atherosclerosis. Lipid rafts, and especially caveolae, are enriched in endothelial cells, and down-regulation of the caveolin-1 gene may provide protection against the development of atherosclerosis. There is substantial evidence that exposure to environmental pollution is linked to cardiovascular mortality, and that persistent organic pollutants can markedly contribute to endothelial cell dysfunction and an increase in vascular inflammation. Nutrition can modulate the toxicity of environmental pollutants, and evidence suggests that these affect health and disease outcome associated with chemical insults. Because caveolae can provide a regulatory platform for pro-inflammatory signalling associated with vascular diseases such as atherosclerosis, we suggest a link between atherogenic risk and functional changes of caveolae by environmental factors such as dietary lipids and organic pollutants. For example, we have evidence that endothelial caveolae play a role in uptake of persistent organic pollutants, an event associated with subsequent production of inflammatory mediators. Functional properties of caveolae can be modulated by nutrition, such as dietary lipids (e.g. fatty acids) and plant-derived polyphenols (e.g. flavonoids), which change activation of caveolae-associated signalling proteins. The following review will focus on caveolae providing a platform for pro-inflammatory signalling, and the role of caveolae in endothelial cell functional changes associated with environmental mediators such as nutrients and toxicants, which are known to modulate the pathology of vascular diseases.

Animal models of thrombosis

The thrombotic response to vascular injury is an important clinical problem that mediates most vascular disease complications. Thrombus formation involves an integrated response that is influenced by blood flow, multiple cell types, and numerous circulating factors. As a result, modeling of this complex response using in-vitro or in-silico strategies is insufficient. The use of animal models of thrombosis provides a critical tool for the discovery and initial testing of novel therapies for vascular thrombosis. The literature from 2008 to the present provides significant advances in regard to novel models of arterial thrombosis, novel mechanisms underlying thrombus formation, new models and mechanisms related to thrombotic stroke, and preclinical advances in therapeutics for vascular thrombosis. The formation of occlusive thrombi is complex, involving the integration of many molecular interactions and cell types at the site of vascular injury. The identification of strategies to suppress occlusive thrombus formation without undermining normal hemostatic function is the primary goal of this area of study.

Progressing From Risk Factors to Omics

Many factors contribute to the development of clinical atherosclerotic disease in adults. Observational studies conducted from the late 1940s onward have helped us to identify cigarette smoking, cholesterol levels, diabetes, blood pressure, and other factors as important determinants of cardiovascular disease (CVD) outcomes.1,2 The effects are multiplicative. For example, smoking, hypertension, and diabetes each double the risk of a heart attack, and having all 3 factors can lead to a risk that was ≈8 times that of an adult of similar age and sex who did not have any of the factors.3 A major focus in the earlier population and clinical studies was identification of persons at increased risk before the clinical atherosclerotic event. Less attention has been directed toward other types of events, such as occurrence of a myocardial infarction in persons presenting with chest pain, recurrent CVD events, and long-term vascular disease complications such as cardiac failure. The determinants of these vascular events are likely to include some of the classical risk factors, but new factors will no doubt be important as well. Improvements in outpatient and inpatient care, diagnosis, and biomarker discovery have reshaped the landscape. It is possible to visualize subclinical CVD with modern atherosclerotic imaging techniques such as carotid intima-media thickness and arterial calcification assessments. Clinical chemists and geneticists identify new biomarkers that promise to help refine assessments of CVD risk, but it is not clear how such tests should be used for research or for clinical care. This article addresses several of the questions posed above and takes the perspective of research and care for clinical atherosclerotic disease, emphasizing the progress we have made from traditional risk factor assessment to the present time that includes newer assessment methods such as genomics, metabolomics, and predictive medicine. ### Traditional Risk Factors for Cardiovascular Disease The traditional risk factors include cholesterol, blood …

Abstract 1129: Obesity-related Elevations in Soluble P-selectin are Derived From Endothelium and Dependent on Expression of Leukocyte P-selectin Glycoprotein Ligand-1

Background : Obesity is associated with proinflammatory changes and an increased risk for vascular disease complications. The tissue source and mechanism by which soluble P-selectin (sPsel) is generated in obesity are unclear. Methods and Results : Soluble p-selectin (sPsel) levels were measured in the circulation from lean wild type and obese leptin receptor deficient mice (LepR−/−) at 4 and 10 weeks of age. In wild-type mice body weight increases from 13+/−2 to 20+/−3 grams over this time period while the body weight increases from 15+/−2 to 38+/−5 grams in LepR−/− mice. At 4 weeks of age sPsel levels were 103+/−8mg/mL in wild-type mice vs. 138+/−9 ng/mL in LepR−/− mice, p=0.048. By 10 wks of age sPsel increased to 112 +/− 2 in wild-type mice and 182 +/− 9 in LepR−/− mice, p=0.00005. In order to determine if the obesity-induced rise in sPsel is regulated by leukocyte Psgl-1, bone marrow transplantation was performed from Psgl+/+ or Psgl−/− donors into irradiated LepR−/−recipients. At 4 weeks post-transplant, sPsel levels were 166 +/−6 ng/mL in LepR−/− mice receiving Psgl+/+ marrow and 45 +/− 4 ng/mL in LepR−/− mice receiving Psgl−/− marrow, p=0.0000004. In order to determine if the sPsel in LepR−/− mice originated from the endothelium versus platelets, we transplanted Psel−/− bone marrow into irradiated LepR−/−mice. At 4 weeks post transplant, sPsel levels were 153 +/−3 ng/mL in LepR−/− mice receiving Psel−/− bone marrow and were not significantly different from LepR−/− mice receiving Psel+/+ bone marrow (166 +/−6 ng/mL, p=0.06). By 10 weeks post transplant, mice gained even more weight and levels were 377+/−51 ng/mL in LepR−/− mice receiving Psel+/+ bone marrow and 370+/−73 ng/mL in LepR−/− mice receiving Psel−/− bone marrow, p=0.87. Conclusions : These data suggest that the increase in sPsel observed in obesity is primarily derived from the endothelium and that this process is regulated by leukocyte Psgl-1.

Plasminogen Activator Inhibitor-1 in Vascular Thrombosis

Thrombotic complications of vascular disease constitute the leading cause of morbidity and mortality in much of the developed world. Current drug therapies available to treat the thrombotic component of arterial and venous vascular complications remain limited. Novel safe and effective treatment strategies to reduce formation of occlusive thrombosis will likely have a major impact on reducing the economic burden of vascular disease on the healthcare system. Enhancing endogenous fibrinolysis by targeting plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of circulating plasminogen activators, has been shown to be effective in markedly attenuating the formation of arterial and venous occlusive thrombosis in animal models. In addition, animal and human studies of PAI-1 deficiency indicate that spontaneous bleeding complications associated with even complete PAI-1 deficiency would be rare. Patients most likely to benefit from PAI-1 inhibition would be those at high risk for vascular events where PAI-1 is elevated, such as is observed in obesity, diabetes and the metabolic syndrome. Since obesity and metabolic syndrome are now epidemic, and will likely have a major adverse impact on vascular thrombotic events, it may be time to test the clinical effectiveness of PAI-1 inhibition in a patient population at high risk for vascular thrombosis.